The Journal of Experimental Medicine
Aegean Conferences: 2009 Conferences
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Published 6 September 2005. doi:10.1084/jem.20050607
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 5, 663-671
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ARTICLE

 MT1-matrix metalloproteinase directs arterial wall invasion and neointima formation by vascular smooth muscle cells

Sergey Filippov1, Gerald C. Koenig2, Tae-Hwa Chun1, Kevin B. Hotary1, Ichiro Ota1, Thomas H. Bugge3, Joseph D. Roberts2, William P. Fay2, Henning Birkedal-Hansen4, Kenn Holmbeck4, Farideh Sabeh1, Edward D. Allen1, and Stephen J. Weiss1

1 Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
2 Division of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
3 Protease and Tissue Remodeling Unit, National Institute of Dental and Craniofacial Research, Bethesda, MD 20892
4 Matrix Metalloproteinase Unit, National Institute of Dental and Craniofacial Research, Bethesda, MD 20892

CORRESPONDENCE Stephen J. Weiss: sjweiss{at}umich.edu

During pathologic vessel remodeling, vascular smooth muscle cells (VSMCs) embedded within the collagen-rich matrix of the artery wall mobilize uncharacterized proteolytic systems to infiltrate the subendothelial space and generate neointimal lesions. Although the VSMC-derived serine proteinases, plasminogen activator and plasminogen, the cysteine proteinases, cathepsins L, S, and K, and the matrix metalloproteinases MMP-2 and MMP-9 have each been linked to pathologic matrix-remodeling states in vitro and in vivo, the role that these or other proteinases play in allowing VSMCs to negotiate the three-dimensional (3-D) cross-linked extracellular matrix of the arterial wall remains undefined. Herein, we demonstrate that VSMCs proteolytically remodel and invade collagenous barriers independently of plasmin, cathepsins L, S, or K, MMP-2, or MMP-9. Instead, we identify the membrane-anchored matrix metalloproteinase, MT1-MMP, as the key pericellular collagenolysin that controls the ability of VSMCs to degrade and infiltrate 3-D barriers of interstitial collagen, including the arterial wall. Furthermore, genetic deletion of the proteinase affords mice with a protected status against neointimal hyperplasia and lumen narrowing in vivo. These studies suggest that therapeutic interventions designed to target MT1-MMP could prove beneficial in a range of human vascular disease states associated with the destructive remodeling of the vessel wall extracellular matrix.

Abbreviations used: 2-D, two-dimensional; 3-D, three- dimensional; BrdU, bromodeoxyuridine; FGF, fibroblast growth factor; MMP, matrix metalloproteinase; MT1, membrane type I; PCNA, proliferating cell nuclear antigen; PDGF, platelet-derived growth factor; TIMP, tissue inhibitor of metalloproteinases; VSMC, vascular smooth muscle cell.


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